This proposal is closely aligned with the Research Theme: "Translating Basic Science Discoveries into New and Better Treatments". The USA is in the midst of an epidemic of obesity that is causing a great deal of mortality and morbidity due to its associated conditions: hypertension, type 2 diabetes and certain cancers. It is also putting a great strain on our health care system. At the present time, there is no generally effective medical therapy for obesity that can augment ongoing efforts to educate the public about diet and exercise regimens. This proposal is aimed at driving therapeutics for human obesity forward, based on modulation of brown fat biology. The last several years have seen breakthroughs in the science of brown fat, a cell-type that plays a critical role in controlling metabolic rates and fighting obesity. Significant deposits of brown fat have been identified in normal healthy humans, and a major transcriptional regulator of brown fat, PRDM16, has been identified. This proposal is focused on developing the science and therapeutic approaches to human obesity, based on the control of brown fat formation and function. Our first Aim will investigate regulation of whole body energy homeostasis via transgenic manipulation of PRDM16, a transcriptional co-regulator that we discovered in 2007 as a dominant regulator of brown fat cell determination. A second Aim will isolate and characterize a second kind of brown fat cell that can reside in white adipose tissues and has substantial thermogenic capacity. Our third Aim will drive translation of our newly acquired knowledge about the role of the nuclear receptor PPAR3 in brown fat and thermogenesis directly into therapeutics. We will combine structure-based methods for chemical screening and compound optimization, with this new biochemical information, to develop PPAR3 ligands that have a preferential effect on brown fat development and function. We will develop compounds that have minimal properties of a classic PPAR3 agonist, but retain the ability to modulate the "browning" of certain white fat cells and stimulate brown fat-mediated energy expenditure in vivo. The ability to treat obesity in animal models will also be investigated with the new compounds. In our final Aim, we will utilize our extensive data concerning brown fat gene expression to investigate the secreted proteins of brown fat that are regulated during thermogenesis. We have already identified several such molecules and will examine their ability to control/affect brown fat cell differentiation and a thermogenic gene program in brown fat and subcutaneous white fat. PUBLIC HEALTH RELEVANCE: The rising tide of obesity in the USA presents a huge threat to the health of the American public, through its associated conditions: hypertension, diabetes and cardiovascular disease. This proposal is centered on therapeutic targeting of brown fat, a key part of the body's natural defense against obesity. Improvements in our ability to regulate pathways of energy expenditure mediated by brown fat promise to relieve the disease burden of the American population and lower healthcare costs in the USA.